Ординатура / Офтальмология / Английские материалы / Ocular Pathology_6th edition_Yanoff, Sassani_2009
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Melanotic tumors of the uvea 701
A B
D
C
Fig. 17.31 Effects of choroidal nevus on overlying retina. A, Juxtapapillary nevus with marked degeneration of overlying retina. B, Bottom demonstrates transitional area between normal neural retina (right side) and degenerated retina (left side). Top shows degenerated neural retina at increased magnification. C, Neural retinal changes caused patient to have absolute scotoma, rare with nevus. D, Wilder elastic stain shows effects of nevus on choriocapillaris; bottom: choriocapillaris shows large lumina in normal choroid; top: choroidal nevi has markedly narrowed the lumina. (A– C, Modified from Naumann G et al.: Am J Ophthalmol 62:914. © Elsevier 1966. D, modified from Naumann G et al: Arch Ophthalmol 76:784, 1966. © American Medical Association. All rights reserved.)
1.In general, nevus cells are plumper than normal melanocytes of the choroid and ciliary body (i.e., they are atypical benign-appearing melanocytes).
2.The four types of uveal nevus cells are (see Fig. 17.29):
a.Plump, polyhedral (see also Fig. 17.51C)
1). This is the most common type and the “typical” nevus contains a majority of these cells.
2). The cell is maximally pigmented.
3). A nevus made up exclusively of this cell is called a melanocytoma (magnocellular nevus).
b.Slender, spindled
1). This is the second most common cell type. 2). It contains little or no pigment.
Often, slender, spindled nevus cells may be seen mixed with the plump cells, or separate from them in a location next to the sclera.
c.Plump, fusiform, and dendritic—these are less pigmented than plump, polyhedral nevus cells, but more pigmented than slender, spindled nevus cells.
d.Balloon cells
1). Balloon cells are large cells with abundant, foamy cytoplasm.
2). Similar cells may be found in cutaneous and conjunctival nevi.
702 Ch. 17: Ocular Melanocytic Tumors
3.Congenital ocular or oculodermal melanocytosis is a di use nevus of the uvea composed primarily of plump, polyhedral nevus cells.
Rarely, the melanocytosis may have a segmental distribution (see p. 671 in this chapter).
E.Microcirculation—the only vascular pattern present in nevi is that of normal vessels.
Vascular patterns seen in melanomas (see Figs 17.42 and 17.43), that is, zones of avascularity (silent pattern), straight pattern, parallel pattern with cross-linking, arcs (fragments of curved vessels or incompletely closed loops), loops (island of tumor surrounded by a large, closed vascular loop), and networks (back-to-back adjacent loops), are not present in nevi.
F.E ects of nevus on neighboring tissues
1.Nevi frequently narrow the overlying choriocapillaris, and, rarely, may completely obliterate it (see
Fig. 17.31).
Slight degeneration, proliferation, or reactive deposition by RPE may occur. Frequently (approximately 40%), they induce overlying drusen formation (see Fig. 17.30).
2.They may cause overlying outer neural retinal
changes that are usually minimal.
Rarely, they cause definite disturbances of rod and cone, or outer nuclear layer (see Fig.
17.31).
3.Central serous choroidopathy (retinopathy) and subretinal neovascularization may rarely occur.
G.Uveal nevi are probably the precursor of most uveal melanomas (see later)
H.Uveal nevi are increased in eyes that contain uveal melanomas.
II. Bilateral di use melanocytic proliferations (BDUMP)
A.BDUMP is associated with systemic malignant neoplasms, mainly poorly di erentiated ovarian or uterine carcinomas in women, and lung carcinomas in men.
B.Severe visual loss may occur, sometimes antedating the development of the uveal tumors.
C.The signs of BDUMP are:
1.Multiple, round or oval, subtle red patches at the level of the RPE, mainly in women, with a mean age of 63 years.
2.A striking fluorescein angiography pattern of multifocal areas of early hyperfluorescence corresponding to the red patches
3.Development of multiple, slightly elevated uveal melanotic tumors, plus di use thickening of the uvea
4.Exudative neural retinal detachment
5.Rapid progression of cataracts
III. Mesectodermal leiomyoma (see p. 350 in Chapter 9)
IV. Malignant melanoma
A.General information
1.The median age is 60.4 years (it is rare in children, but may even be congenital).
2.There is a slight preponderance of melanomas in men.
3.White patients have intraocular melanomas more frequently than black patients in a ratio of 15 :1.
a.In addition, patients of Japanese, Chinese, Hispanic, and Native American origin have a lower incidence of choroidal melanoma than do white patients.
b.A case of a choroidal melanoma has been reported in an African-American albino.
4.Bilaterality or multifocal origin is extremely rare.
5.Uveal melanomas are slightly more prevalent in individuals with blue or gray irises than in those with brown irises.
a.Increased choroidal pigmentation secondary to increased density of pigmented choroidal melanocytes may be a risk factor for the development of posterior uveal melanoma. Similarly, melanoma patients with light iris color are more likely to have darker choroidal pigmentation than control patients.
In an Australian population, nonbrown eye color has been associated with increased risk of iris melanoma. Eye color is also the strongest constitutional predictor of choroidal and ciliary body melanoma in that population.
6.An increased risk factor for uveal melanoma is an occupation that involves intense exposure to ultraviolet light. Sun exposure has been associated with increased risk of choroidal and ciliary body melanoma in Auatralia.
7.The overall incidence of uveal melanomas in a white population is approximately 5 to 7 per million per year. For the age group beyond 20 years, an annual incidence rate of approximately 7.5 per million per year, and beyond 50 years an annual incidence rate of approximately 21 per million per year is expected.
Therefore, approximately 1 of 2500 white patients will have a uveal melanoma during his or her lifetime.
The overall mean age-adjusted incidence of uveal melanomas in the United States is 4.3 per million with a greater rate in men and a preponderance in the white population (97.8%).
8.Heredity and bilaterality are not important factors.
9.Bilateral primary melanoma may occur in approximately 1.8% of all patients who have primary uveal melanoma. Extremely rarely, more than one primary uveal melanoma can occur in one eye.
10.Familial cases have also been reported.
11.Primary choroidal melanoma can occur in a patient who has had a previous cutaneous melanoma.
12.For sites of malignant melanoma within the eye, see Table 17.3.
13.Classification of tumors as to size is shown in Table
17.4.
14.The finding of activation of extracellular-regulated kinase in uveal melanoma suggests a causative role
Melanotic tumors of the uvea 703
TABLE 17.3 Site of Malignant Melanomas in the Eye
Location |
Anterior* |
Equatorial |
Posterior |
Anterior–Posterior† |
Total |
|
|
|
|
|
|
|
|
Superior |
3 |
|
3 |
2 |
8 |
|
Inferior |
2 |
|
2 |
1 |
5 |
|
Temporal |
2 |
1 |
9 |
5 |
17 |
} |
Inferotemporal |
5 |
3 |
2 |
|
10 |
|
|
|
|
|
|
51 |
|
Superotemporal |
2 |
|
12 |
1 |
15 |
|
Macula |
|
|
9 |
|
9 |
|
Nasal |
3 |
2 |
7 |
3 |
15 |
} |
Inferonasal |
1 |
|
3 |
1 |
5 |
|
|
|
|
|
|
31 |
|
Superonasal |
5 |
|
4 |
2 |
11 |
|
Peripapillary |
|
|
2 |
|
2 |
|
Whole eye |
|
|
|
3 |
3 |
|
Total |
23 |
6 |
53 |
18 |
100 |
|
|
|
|
|
|
|
|
*Includes ciliary body and choroid anterior to equator; does not include iris.
†Diffuse or large neoplasms extending from ciliary body or ora serrata to posterior choroid.
(From Yanoff M, Zimmerman LE: Cancer 20:493, 1967. © American Cancer Society. Adapted by permission of Wiley-Liss, Inc, a subsidary of John Wiley & Sons. Inc.)
TABLE 17.4 Classification of Tumor as to Size*
|
Largest Diameter |
Largest Elevation |
|
(mm) |
(mm) |
|
|
|
Very small |
≤7.0 |
≤2.0 |
Small |
7.7–10.0 |
2.1–3.0 |
Medium |
10.1–15.0 |
3.1–5.0 |
Large |
>15.0 |
>5.0 |
|
|
|
*The largest dimension of a tumor is the most important measurement (i.e., a tumor 15.5 × 14.0 × 4.0 mm would be classified as “large”).
for mitogen-activated protein kinase (MAPK) activation in uveal melanoma independent of activating v-raf murine sarcoma viral homolog or RAS mutations.
B.Clinical presentation
1.A mass found on routine examination or after a complaint of blurred vision is the most frequent presentation (Fig. 17.32).
Fluorescein angiography, ultrasonography, computed tomography, and magnetic resonance imaging, and, less
often, 32P tests may help to identify and clarify intraocular masses.
2.Episcleral vascular injection may occur overlying a ciliary body melanoma (Fig. 17.33A and B).
Some patients with the condition have been treated for chronic conjunctivitis until the melanoma was discovered by adequate ophthalmoscopy.
3.A ciliary body melanoma may cause decreased intraocular pressure. Conversely, tumors that infiltrate the anterior-chamber angle or tumors undergoing necrosis resulting in liberation of pigment
(melanomalytic glaucoma) may present with elevated intraocular pressure.
a.Ring melanoma
1). This condition has a poor prognosis.
2). The mean is 8 clock-hours of ciliary body involvement at presentation,with 30% having 360° of involvement.
3). Mean tumor thickness: 8 mm.
4). Shallow anterior chamber present in 48%, anterior-chamber inflammation in 22%, cataract in 39%, lens indentation in 35%, and lens subluxation in 13%. A “sentinel” episcleral blood vessel is found in 74%.
5). Multilobulation present in 83%.
704 Ch. 17: Ocular Melanocytic Tumors
A C
f
ts
o
l
i
B D
Fig. 17.32 Choroidal malignant melanoma. A, The patient had a slowly enlarging choroidal tumor, followed over a 9-year period. Tumor initially found on routine examination. B, Magnetic resonance imaging (T1-weighted) shows the choroidal tumor just above the optic nerve. T2-weighted imaging showed that the tumor became less white, characteristic of a malignant melanoma (hemangioma of the choroid, for example, becomes whiter with T2 imaging) (f, frontal lobe; t, thickened choroid; s, superior rectus muscles; o, optic nerve; i, inferior rectus muscles; l, lens). C, The enucleated eye shows the gross appearance of the tumor. D, A histologic section demonstrates a malignant melanoma of the spindle-B type.
6). There is ultrasonic hollowness with intrinsic pulsations in 100% of cases.
7). The most common histopathologic type is mixed (74%), and metastasis develop in 52% of all patients after a mean follow-up of 55 months.
8). Regional lymph node metastasis may occur following filtration surgery for glaucoma associated with ring melanoma. Therefore, such tumors should be excluded before filtra-
tion surgery is performed for unilateral “pigmentary glaucoma.”
b). Subconjunctival spread of ciliary body melanoma has been found after glaucoma filtration surgery in a patient with an underlying ciliary body melanoma.
4.The patient may present with an episcleral extension of a uveal malignant melanoma that may simulate a conjunctival lesion (see Fig. 17.33C, D, and E).
Melanotic tumors of the uvea 705
A B
C D
Fig. 17.33 Mistaken diagnoses. A, Patient had been treated for chronic conjunctivitis. B, Needle biopsy of superotemporal pigmented tumor was positive for melanoma (hemorrhage result of biopsy). C, Another patient referred in because of epibulbar mass at limbal region of right eye. D, After dilatation, ciliary body tumor seen. Eye was enucleated. E, Periodic acid–Schiff-stained histologic section shows a ciliary body malignant melanoma has infiltrated Schlemm’s canal and collector channels, and has extended subconjunctivally. (B, Courtesy of Dr. JJ Augsburger.)
E
5.Vitreous hemorrhage (see p. 716 in this chapter)
The Knapp–Ronne type of malignant melanoma of the choroid is characterized by a location near the optic disc, early growth through the neural retina, and a structure showing both bloodless and blood-filled cavernous spaces. It presents with a massive hemorrhage into the vitreous that may result in hemosiderosis bulbi and heterochromia iridum.
6.An RPE detachment or central serous choroidopathy (retinopathy; Fig. 17.34) may accompany a peripheral uveal malignant melanoma.
7.CME (see Fig. 17.34; almost identical to that seen in Irvine–Gass syndrome, diabetic retinopathy, hypotony, and uveitis) may be found.
8.Neural retinal detachment, present in approximately 75% of cases (see p. 716 in this chapter), and occasionally, may mask the underlying melanoma.
706 Ch. 17: Ocular Melanocytic Tumors
A
mc
p
p
mc
B
Fig. 17.34 Mistaken diagnoses. A, Patient presented with blurred vision caused by central serouslike choroidopathy. The eye was enucleated because of a peripheral choroidal melanoma. Histologic section shows serous fluid under the macular retina. B, Another patient had a peripheral choroidal melanoma and clinical and fluorescein appearance characteristic of cystoid macular edema (inset). Electron micrograph from Henle fiber layer of same eye shows swollen Müller cells (mc). Intercellular spaces (arrows) are normal. Adjacent photoreceptor (p) axons (Henle fibers) appear relatively normal. (Modified from Fine BS, Brucker AJ Jr: Am J Ophthalmol 92:466. © Elsevier 1981.)
Extremely rarely, a horseshoe retinal tear may accompany the retinal detachment.
9.An unusual presentation is with a choroidal detachment.
10.Ocular inflammation may occur (Fig. 17.35), but is much less common than with retinoblastoma.
11.Glaucoma (see pp. 644 and 650 in Chapter 16).
a.Acute angle closure glaucoma may result from choroidal melanoma.
12.Opaque media (see p. 720 in this chapter)
13.A uveal melanoma may originate in or invade the iris and produce heterochromia iridum.
Heterochromia iridum may also result from hemosiderosis bulbi after a vitreous hemorrhage associated with a uveal melanoma.
Melanotic tumors of the uvea 707
A B
Fig. 17.35 Necrotic uveal melanoma. A, The patient presented with recent onset of blindness, pain, redness, and chemosis. Examination by ultrasonography showed a solid tumor. The eye was enucleated. B, A histologic section shows that the typical “mushroom” tumor had undergone spontaneous and complete necrosis, making identification of the melanoma cell type almost impossible. This type, therefore, is called the necrotic cell melanoma. Completely necrotic melanomas often present clinically, as this patient’s did, with the appearance of inflammation.
14.A malignant melanoma may simulate a postoperative choroidal detachment.
15.Metastases are usually a late manifestation of uveal melanomas, whereas frequently, they are an early manifestation of skin melanomas (see Fig. 17.7).
16.Factors associated with a worse prognosis for survival following enucleation for choroidal and ciliary body melanomas are largest basal diameter (LBD), nonspindle cell type, and anterior location.
17.During the period 1955 to 2000 there was no apparent change in the clinical and histopathological presentation of choroidal or ciliary body melanomas.
18.The manner in which suspected melanomas of the choroid and ciliary body are managed has changed significantly over the past 30 years. During this period, an increased emphasis has been placed on the importance of tumor growth as an indication of a possible aggressive character for the lesion. Conversely, such lesions are not viewed as “ocular emergencies,” thereby providing time for sober clinical deliberation and thorough evaluation before a course of therapy is chosen.
For example, in one study by Gass,* 116 suspected choroidal or ciliary body melanomas were observed for evidence of tumor growth. During a minimum observation period of 5 years, no tumor growth was observed in 69 patients, and none displayed evidence of metastatic disease. The tumor grew in 47 patients, resulting in enucleation in 35 individuals. In general, death from metastasis was associated with tumors that were observed to grow, particularly those having epithelioid cells. The period of observation was not judged to contribute to increased tumor mortality.
*Gass JD: Observation of suspected choroidal and ciliary body melanomas for evidence of growth prior to enucleation. Retina 23:523, 2003.
C.Histogenesis (theories)
1.Mesodermal: the tumor arises from mesodermal elements in the uvea, hence the old name melanosarcoma.
2.RPE: the melanoma arises from the RPE.
3.Neural: the melanoma arises from Schwann’s cells associated with the ciliary nerves.
4.Nevoid: the melanoma arises from a pre-existing nevus. Most evidence points to this theory (i.e., the vast majority of uveal malignant melanomas arise
from pre-existing nevi; Fig. 17.36).
Five risk factors for growth of small (≤3 mm in thickness) melanocytic choroidal tumors are:
1). Tumor thickness greater than 2 mm
2). Posterior tumor margin touching disc
3). Visual symptoms
4). Orange pigment
a.An apparently stable and nonmalignant choroidal nevus can produce overlying orange pigment that can even result in massive pigment accumulation, which can form a pseudohypopyon.
5). Subretinal fluid
b.Optical coherence tomography can be helpful in assessing for subretinal fluid in ocular melanocytic tumors, and in distinguishing from chronic retinal changes that may overly such lesions.
5.De novo (i.e., the melanoma arises in the uvea without any obvious antecedent cause)
D.Callender classification and prognosis (Figs 17.37 to 17.40)
The classification is used specifically for ciliary body and choroidal malignant melanomas; it may be applied to iris but not to conjunctival or skin malignant melanomas. Japanese patients have a worse prognosis than that reported in the
708 Ch. 17: Ocular Melanocytic Tumors
A B
C D
Fig. 17.36 Histogenesis. A, Choroidal nevus just above the central fovea of the left eye was noted in 1969. B, Rapid growth occurred almost 4 years later. Eye enucleated. Histology showed a heavily pigmented choroidal melanoma. C, Histologic section of another eye (top) shows a mushroomshaped choroidal melanoma with a long “tail” extending to the right. Increased magnification of the tail (bottom) demonstrates cytology indistinguishable from a choroidal nevus. D, A mushroom-shaped choroidal melanoma is present in an eye with congenital ocular melanocytosis (i.e., a maximally pigmented, diffuse nevus of the uvea). The inset (bleached section) shows the innocuous nevus cells at the base of the melanoma.
(C, Reproduced from Yanoff M, Zimmerman LE: Cancer 20:493, 1967. © American Cancer Society. Adapted by permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc; D, Adapted from Yanoff M, Zimmerman LE: Arch Ophthalmol 77:331, 1967. © American Medical Association. All rights reserved.)
white population. Melanomas may have a poor prognosis because the melanoma cells seem capable of killing the body’s immune cells (activated T lymphocytes) that attack them. The melanoma cells bear on their surface Fas (also called Apo-1), which can initiate cells to commit suicide by a process called apoptosis. When Fas binds to another molecule called Fas ligand (FasL), which occurs mainly on activated T lymphocytes, Fas triggers a series of events inside the immune cell that leads to its suicide (i.e., apoptosis).
Decreased expression of human leukocyte antigen (HLA) class I antigen is usually associated with nonuveal melanoma tumor progression. Paradoxically, loss of HLA I antigen in uveal melanoma is not associated with tumor cell escape and a worse survival.
1.Spindle-A (see Figs 17.37A, 17.38A, and 17.39B)
a.Spindle-A is the second rarest type of melanoma (5%), and is made up of cohesive cells that
Melanotic tumors of the uvea 709
A B C
Fig. 17.37 Callender classification. A, Spindle-A cells are shown in longitudinal and transverse cross-sections. The cells are cohesive and have poorly defined cell borders. The nuclei contain nuclear folds that appear as dark stripes parallel to the long axis of the nuclei. The stripe is caused by infolding of the nucleus, as noted in the cross-section. B, Spindle-B nuclei are larger and plumper than spindle-A nuclei and contain prominent nucleoli rather than nuclear folds. The cells, similar to spindle-A, are cohesive and have poorly defined cell borders. C, Epithelioid cells are not cohesive, have distinct cell borders, and show large oval nuclei that contain prominent nucleoli. The cells are larger than spindle-A and spindle-B cells.
contain small, spindled nuclei having a central dark stripe (caused by a nuclear fold) but no distinct nucleoli; the cytoplasm is indistinct and has no easily identifiable cell borders.
The dark stripe does not always occur, but when it does, it is quite helpful in classification. A tumor is classified as spindle-A when it is estimated to contain no more than 5% spindle-B cells and no epithelioid cells. Some, if not all, of the tumors previously classified as spindle-A are benign, and really should be called spindle cell nevi.
b.Mitotic figures are extremely rare.
c.The survival rate is approximately 92%.
2.Spindle-B and fascicular (see Figs 17.37B, 17.38B and D, 17.39C, and 17.40A and B)
a.Spindle-B is common (39%), and is made up of cohesive cells that contain prominent spindled nuclei with distinct nucleoli; the cytoplasm is indistinct and has no easily identifiable cell borders.
b.Spindle-B cells have decreased pleomorphism, and nuclear area compared with epithelioid cells.
A tumor is classified as spindle-B when it contains more than 5% spindle-B cells, but no epithelioid cells. Because if enough sections are studied, most tumors composed of spindle cells contain both A and B cells, the tumors should probably simply be called spindle cell type.
c.In approximately 6% of spindle-B cell malignant melanomas, the spindled cells form a palisaded arrangement called a fascicular pattern.
The cell type of the fascicular pattern, however, remains spindle-B. Rarely, epithelioid cells are admixed within the fascicular pattern; the tumor should then be diagnosed as a mixed-cell type.
d.Mitotic figures are rare.
e.The survival rate is approximately 75%.
3.Epithelioid (see Figs 17.37C, 17.38C, 17.39D, and
17.40C and D)
a.Epithelioid is the rarest type (3%), and is made up of noncohesive cells that contain large, round nuclei with prominent nucleoli (frequently pink) and abundant eosinophilic cytoplasm with distinct cell borders.
b.Epithelioid cells have increased pleomorphism and nuclear area compared with spindle-B cells.
A small type of epithelioid cell that contains less cytoplasm, a smaller nucleus, and less distinct cell borders than the classic epithelioid cell is now recognized. This small intermediate epithelioid cell should not be confused with a “plump” spindle-B melanoma cell.
c.Mitotic figures are common.
d.The survival rate is approximately 28%.
4.Mixed (see Fig. 17.38D)
a.Mixed cell, the most common type (45%), contains both a significant spindle-cell component
(usually spindle-cell B), and an epithelioid cell component.
Mixed cell is not a mixture of spindle-A and spindle-B cells, but of spindle cells and epithelioid cells. A tumor is classified as mixed if only one large, unequivocal epithelioid cell is seen in approximately five fields at a magnification of 400.
b.The survival rate is approximately 41%.
5.Necrotic (Fig. 17.41; see also Fig. 17.35)
a.Necrotic is an uncommon type (7%); the tumor is so necrotic that the cell type is not identifiable.
710 Ch. 17: Ocular Melanocytic Tumors
l
t
m
l
t
A B
C D
E F
Fig. 17.38 Callender classification. A, Spindle-A cells, identified by a dark stripe parallel to the long axis of the nucleus, are seen in longitudinal section (l). They are identified in transverse cross-section (t) by the infolding of the nuclear membrane that causes the dark stripe. B, Spindle-B cells are identified by their prominent nucleoli. Note the mitotic figure (m). Both spindle-A and spindle-B cells tend to be quite cohesive and have poorly defined cell borders. C, Epithelioid cells are the largest of the melanoma cells, tend not to be cohesive, and have irregular shapes and sizes as well as very prominent nucleoli in the large nuclei. D, Some melanomas contain a mixture of spindle cells and epithelioid cells. The left half of this figure is occupied by epithelioid cells and the right half by spindle cells (this is called a mixed-cell melanoma). E, Fascicular pattern always consists of spindle- B cells. F, Higher magnification of another case shows spindle-A and B, and epithelioid cells. Note characteristic nuclear infolding of spindle-A cell. (Courtesy of Dr. Morton Smith.)
Necrosis may lead to large cystic spaces in the tumor or to a large accumulation of eosinophilic debris, sometimes containing cholesterol clefts. Clear cells may occur in necrotic melanomas. Clear cells may also be a predominant component of the melanoma, called a clear-cell variant, and should not be confused with other clear-cell neoplasms metastatic to the uvea (e.g., hypernephroma).
b.Tumor necrosis may be caused by an autoimmune mechanism (a large population of plasma cells in the tumor supports this hypothesis).
c.The survival rate is approximately 41%.
d.Scleritis and episcleritis are statistically associated with total tumor necrosis of choroidal and ciliary body melanomas.